教員業績データベース |
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論文種別 | 原著 |
言語種別 | 英語 |
査読の有無 | 査読あり |
表題 | Trametinib plus 4-Methylumbelliferone Exhibits Antitumor Effects by ERK Blockade and CD44 Downregulation and Affects PD-1 and PD-L1 in Malignant Pleural Mesothelioma. |
掲載誌名 | 正式名:Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 略 称:J Thorac Oncol ISSNコード:1556-1380(Electronic)1556-0864(Linking) |
掲載区分 | 国外 |
巻・号・頁 | 12(3),pp.477-490 |
著者・共著者 | Cho Hiroyuki, Matsumoto Seiji, Fujita Yoshiko, Kuroda Ayumi, Menju Toshi, Sonobe Makoto, Kondo Nobuyuki, Torii Ikuko, Nakano Takashi, Lara Primo N, Gandara David R, Date Hiroshi, Hasegawa Seiki |
発行年月 | 2017/03 |
概要 | INTRODUCTION:Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase pathway plays a critical role in the regulation of tumorigenesis. Hyaluronic acid (HA) is a major component of the extracellular matrix, and elevated HA levels with a concurrent increase in malignant properties are associated with MPM.METHODS:We evaluated the effects of trametinib, a mitogen-activated protein kinase (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo. We studied the effects of trametinib, 4-MU, and their combination on MPM cells by using cell viability assays, Western blot analysis, and a mouse xenograft model.RESULTS:Trametinib and 4-MU exhibited antiproliferative activity in MPM cells. Trametinib blocked MEK-dependent extracellular signal-regulated kinase (ERK) phosphorylation and decreased CD44 expression in a concentration-dependent manner. Trametinib inhibited the expression of Fra-1 (the activator protein 1 [AP1]component), inhibited ERK phosphorylation, and decreased CD44 expression. 4-MU inhibited ERK phosphorylation but not CD44 expression. In a mouse xenograft model, trametinib and 4-MU alone suppressed tumor growth compared with a control. The combination had a greater inhibitory effect than either monotherapy. Immunohistochemical analysis showed that trametinib treatment alone significantly reduced expression of programmed cell death 1 ligand 1. Furthermore, the combination of trametinib and 4-MU resulted in higher expression of programmed cell death 1 and programmed cell death 1 ligand 1 than did the 4-MU treatment alone.CONCLUSIONS:Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted. |
DOI | 10.1016/j.jtho.2016.10.023 |
PMID | 27867002 |